The present invention relates to novel compounds which are inhibitors of the binding of fibrinogen to the Gp IIb/IIIa platelet receptors, and which can be used therapeutically as antithrombotic agents.
In the course of the pathological processes which lead to the formation of a thrombus (clot) and then to its extension, platelet aggregation represents a key step since it is the source of the seriousness of the phenomenon. Specifically, from the initiation of the thrombus, in particular in the arterial blood circulation, the intervention of several interdependent biochemical reactions induces the aggregation of an increasingly large number of platelets via the conversion of the soluble fibrinogen into insoluble fibrin filaments which increase the size of the mass of platelets, first at the actual site of the arterial vascular lesion, and then increasingly into the lumen of the vessel.
In this mechanism of platelet aggregation, activation of the Gp IIb/IIIa receptors is the source of the amplification of the platelet aggregation. Fibrinogen, which can bind via its two dimers to these receptors, amplifies the binding together of the platelets and thus induces the formation of a platelet mass forming a thrombus at the site of rupture of the atheroma plaque.
This mechanism of platelet aggregation is particularly active in all arterial thromboses, whether they appear in the course of performing interventional cardiology (transluminal percutaneous angioplasty; insertion of stents), heart surgery (aorta-coronary bypass; valve surgery), in the course of acute heart diseases (myocardial infarction, unstable angina, acute coronary syndromes, etc.) or in the course of certain cerebral ischaemias, or finally in the course of myocardial ischaemias which may complicate the follow-up of an antithrombotic treatment.
Reducing or preventing the activation of platelets in contact with a broken atherosclerotic plaque thus represents a novel and effective therapeutic approach to the treatment of thrombosis, in particular arterial thrombosis, and thus an efficient means for preventing acute coronary syndromes, including unstable angina and myocardial infarction.
The present invention is directed towards novel competitive inhibitors of the binding of fibrinogen on the Gp IIb/IIIa receptors which can be used as antithrombotic medicinal products.
The present invention is also directed towards providing compounds which can be administered orally, which give a prolonged duration of action and which avoid the risks of bleeding.
One subject of the present invention is compounds of the general formula (I): 
in which:
R1 is chosen from hydrogen, a C1-C4 alkyl group and a phenyl(C1-C4 alkyl) group;
R2 is chosen from hydrogen, a hydroxyl group and a protecting group for the amidino group;
R3 is chosen from the groups of formula:
xe2x80x94NHxe2x80x94COxe2x80x94R6,
R6 being chosen from C1-C4 alkoxy, C3-C7 cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups,
and the groups of formula:
xe2x80x94NHxe2x80x94SO2xe2x80x94R7,
R7 being chosen from:
C1-C5 alkyl groups optionally substituted with one or more groups chosen from halogens, hydroxyl groups and the trifluoromethyl group;
mono- or bicyclic C3-C12 cycloalkyl groups;
mono-, bi- or tricyclic C6-C14 aryl groups;
heteroaryl groups chosen from pyridyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl and isoxazolyl groups;
phenyl(C1-C4)alkyl and naphthyl (C1-C4)alkyl groups;
and the groups of formula: 
in which n=1, 2 or 3;
the aryl or heteroaryl groups of R7 optionally being substituted with one or more groups chosen independently from halogens, C1-C4 alkyl, trifluoromethyl, C1-C4 alkylthio, C1-C4 alkyloxy, C1-C4 alkylsulphonyl, nitro, di ((C1-C4)alkyl)amino, phenyl, naphthyl and heteroaryl groups chosen from thienyl, furyl and pyridyl groups, and from groups xe2x80x94COOR, xe2x80x94CH2xe2x80x94COOR or xe2x80x94Oxe2x80x94CH2COOR, R being a C1-C4 alkyl group.
R4 and R4 are chosen, independently of each other, from hydrogen, a C1-C5 alkyl group or form, together with the nitrogen atom, a group chosen from piperidyl and morpholinyl groups,
and the oxo group is in position 2 or 3 on the piperazine, and the addition salts thereof with pharmaceutically acceptable acids.
As protecting groups for the amidino group, mention may be made of ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and tertbutoxycarbonyl groups.
As examples of aryl groups, mention may be made of phenyl, xcex1-naphthyl, xcex2-naphthyl, fluorenyl and biphenylyl groups.
The C1-C5 alkyl groups may be linear or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.
The C1-C4 alkoxy groups may similarly be linear or branched. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups.
The halogens may be chosen from fluorine, chlorine, bromine and iodine.
The xe2x80x9caddition salts with pharmaceutically acceptable acidsxe2x80x9d denote salts which give the biological properties of the free bases without having an undesirable effect. These salts may be, in particular, those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; acidic metal salts such as disodium orthophosphate and monopotassium sulphate, and organic acids.
The compounds of formula (I) can be prepared by:
a) reacting an acid of formula 
in which Z is a precursor group of a group 
with an amine of formula 
to give a compound of formula 
and
b) converting the group Z into a group 
The acids of formula (II) can be reacted with the amines of formula (III) in a polar solvent such as DMF, THF or ethyl acetate, in the presence of a coupling agent (DCC/HOBT, BOP or isobutyl chloroformate) at a temperature of from 15xc2x0 C. to 50xc2x0 C.
When Z is an Nxe2x89xa1Cxe2x80x94 group, the group Z can be converted into an amidoxime by adding hydroxylamine to the nitrile group in the presence of a suitable base (K2CO3, Et3N or C2H5ONa) in an alcoholic solvent. Hydrogenolysis in the presence of palladium-on-charcoal, in a mixture of acetic anhydride and acetic acid, of the compounds obtained gives the compounds of formula (I) in which R2 is hydrogen.
When Z is an Nxe2x89xa1Cxe2x80x94 group, the group Z can also be converted into an imidate by adding ethanol in the presence of HCl in ethyl acetate. The imidate obtained is then converted into compounds of formula (I) in which R2 is a hydrogen and xe2x80x94NR4R5 is either a piperidyl group or a morpholinyl group, by reaction with the corresponding amine in ethanol/ethyl acetate medium.
The compounds of formula (II) containing a 2-piperazinone group, when Z is a nitrile group, can be obtained according to the following scheme: 
4-Fluorobenzonitrile is reacted with an excess of ethylenediamine in an aprotic solvent to give 4-(2-aminoethyl)benzonitrile which is then mono-alkylated with ethyl bromoacetate in a polar solvent such as ethanol or acetonitrile in the presence of an inorganic base or a tertiary amine. Acylation with chloroacetyl chloride followed by cyclization and hydrolysis give the acid (1).
The compounds of formula (II) containing a 3-piperazinone group, when Z is a nitrile group, can be obtained according to the following scheme: 
4-(2-Aminoethyl)benzonitrile is dialkylated with ethyl bromoacetate; the cyclization is carried out in the presence of a tertiary amine, an inorganic base or a mixture thereof; after hydrolysis, the acid (2) is obtained.
The addition salts are obtained conventionally by reacting the compound of formula (I) with a pharmaceutically acceptable acid in a suitable solvent. conversely, the bases may be obtained from the addition salts by treatment with a strong base.